Poor water solubility of active pharmaceutical ingredients (APIs) is a key challenge in drug discovery and development as it results in low drug bioavailability upon local or systemic administration. Numerous drugs and drug candidates suffer from low aqueous solubility, limiting their bioavailability when administered orally or by other parenteral routes. Besides poor absorption, low aqueous solubility drugs are difficult to formulate as injectables.
Various approaches have been developed to enhance the solubility, dissolution rate, and oral bioavailability of poorly water-soluble drugs such as crystal modification, micronization, amorphization, self-emulsification, cyclodextrin complexation, and pH modification. Another approach is prodrugs, where the active hydrophobic drug is derivatized to a bioavailable hydrophilic precursor that can be converted by endogenous enzymes to the native drug. Prodrugs have been utilized in attempts to “rescue” or “salvage” water insoluble drug candidates or to enhance the usefulness of established drugs.1, 2 Supersaturation has long been proposed as a means to improve the bioavailability of low solubility, high permeability (Biopharmaceutics Classification System Class II) drugs.5, 6 Formulating drug as a high solubility crystalline polymorph or as an amorphous solid has been studied as a means to achieve at least temporary supersaturation in the GI tract.7-9 Solid dispersion of drug in a glassy polymer by spray drying10-12 or by quenching a hot melt13-15 of drug in polymer has also been studied.
Epilepsy affects an estimated 3 million people in the United States, making it second only to stroke for debilitating neurological conditions. Contrary to stroke, which primarily affects the elderly, the majority of patients with epilepsy include children and young adults, a population that may require decades of drug therapy. Conditions such as Status Epilepticus (SE) are emergencies that require fast delivery of a potent antiepileptic drug such as diazepam. Rapid delivery of many of these antiepileptic drugs in ambulatory situations is, however, limited by their low aqueous solubility, so the approach of creating supersaturated solutions of these drugs at the point of administration is attractive.
In an early study, Hou and Siegel demonstrated that adding water to a saturated diazepam-in-water/glycofurol solution drove diazepam into a supersaturated state, which was stable long enough to cross synthetic membranes several fold faster than saturated diazepam.21 Also, a limited clinical pharmacokinetic study provided evidence for rapid absorption of supersaturated diazepam administered intranasally, but the formulation was intolerable to human subjects.22 
With fosphenytoin/alkaline phosphatase as a model prodrug/enzyme system, our group prepared supersaturated aqueous solutions of prodrug-enzyme mixtures at the point of administration, and demonstrated enhanced membrane permeation of the product drug, in this case phenytoin, compared to saturated drug solution, without precipitation (Kapoor M, Siegel R A. Prodrug/Enzyme Based Acceleration of Absorption of Hydrophobic Drugs: An in Vitro Study. Molecular Pharmaceutics. 2013 2013 Dec. 16; 10(9):3519-24). While demonstrating feasibility of the prodrug/enzyme approach, phenytoin is not a suitable candidate for intranasal delivery due to its high dose requirement.
Avizafone is a diazepam prodrug used by the French military to reverse seizures triggered by nerve agents encountered on the battlefield. In a preliminary study in dogs, our group demonstrated that, when administered intranasally, the fraction of the avizafone absorbed and converted to diazepam was only ˜30-45% of the total dose, which rendered avizafone unacceptable for further development in that particular form. It was concluded that the highly water soluble avizafone does not efficiently cross the nasal mucosa. There remains a need for a method of administering avizafone in a manner that delivers parent drug diazepam across mucosal membranes.